Atrial Fibrillation and Revascularization Procedures: Clinical and Prognostic Significance. Incidence, Predictors, Treatment, and Long-Term Outcome.

[This retracts the article on p. 50 in vol. 7.].


Importance of Clinical Features
The clinical characteristics of patients play an important role in the occurrence of AF during and after a PCI procedure. Kinjo et al. 4 assessed the prognostic significance of AF and atrial flutter in patients with acute MI that had been treated with PCI. In their study, patients with AF were older and in higher Killip classes, had higher rates of previous MI and previous cerebrovascular accident, had systolic blood pressures of less than 100 mmHg and heart rates' value higher than 100 beats/min, were less likely to smoke, and had higher prevalence of multivessel disease and poorer reperfusion of infarct-related artery than those without AF. AF was a common complication in patients with MI who were treated with PCI and independently influenced 1-year mortality. Cardiogenic shock, congestive heart failure, cardiac rupture, ventricular tachycardia and/or ventricular fibrillation, and stroke occurred more often in patients with AF than in those with-out AF. No significant difference was observed in the rates of recurrent infarction or recurrent ischemia. The unadjusted in-hospital mortality rate was significantly higher in patients with AF than in those without AF. But, after adjustment for demographic characteristics and clinical factors, AF was not associated with in-hospital mortality. Furthermore, when stratified by the timing of AF, both AF at admission and AF that developed during hospitalisation were not independent predictors for in-hospital mortality. Therefore, AF was not significantly associated with in-hospital mortality in patients with MI who underwent PCI. One-year mortality was higher in patients with AF than in those without AF. Most deaths were due to cardiovascular causes. Patients with AF had a greater incidence of death due to pump failure than those without AF. After adjustment for demographic characteristics and clinical factors, patients with AF remained at significantly greater risk for mortality at 1 year. Furthermore, when stratified by the timing of AF, AF during hospitalisation was independently associated with one year mortality, but AF at admission was not. The one year mortality of patients discharged alive was higher in those with AF than in those without AF. After adjustment for demographic characteristics, clinical factors, and antiarrhythmic drug use at discharge, patients with AF remained at significantly greater risk for mortality at one year 4 .

Importance of Electrophysiological Predictors
Inhomogeneous prolongation of sinus impulses may predict the recurrence of AF. In two recent trials from Dilaveris et al. and Gorenek et al. 5,6 , P wave dispersion (P dispersion) was evaluated; it is commonly defined as the difference between the maximum and the minimum P wave duration, and maximum P wave duration (P maximum). In these trials, age, history of organic heart disease, P maximum, minimum P wave duration, and P dispersion were found to be significant univariate predictors of recurrent AF, whereas only P maximum and age remained significant independent predictors of frequent AF paroxysms in the multivariate analysis. Authors concluded that advanced age and prolonged P wave duration may be used as predictors of frequently relapsing AF. The presence of heterogeneous structural and electrophysiological properties in different portions of an atrium prone to fibrillate, may result in an inhomogeneous and discontinuous prolongation of sinus impulses 7 .
Electrophysiological studies have demonstrated that individuals with a clinical history of AF have a significantly longer intra-atrial and inter-atrial conduction time of sinus impulses [8][9][10] . This has been confirmed by the finding of P-wave prolongation on 12-lead surface ECG and signal-averaged ECG recordings [11][12][13] . The importance of P-wave dispersion in predicting recurrence of AF in patients with paroxysmal AF has also been elucidated 5,14 . Thus, P-wave signal-averaged ECG could be useful to identify patients at risk for recurrence of AF after internal cardioversion 15 .
Ozmen et al. 16 investigated the effects of angioplasty induced-ischemia on atrial conduction as estimated by P-wave maximum and P-wave dispersion. The study consisted of 67 consecutive patients (41 men, mean age 58±11 years) with single vessel coronary artery disease who underwent elective single vessel coronary angioplasty (left anterior descending (LAD) coronary artery in 28 patients, the right coronary artery (RCA) in 22 patients and the left circumflex coronary artery (LCx) in 17 patients). All patients underwent 12-lead surface ECG before the first inflation (baseline) and then 60s after intra-coronary balloon inflation. The maximum P wave duration, the minimum P wave duration, and P wave dispersion (Pd = Pmax -Pmin) were calculated from 12-lead surface ECG. Both values of P maximum and P dispersion were significantly higher during balloon occlusion compared with the baseline condition in coronary dilatation procedures. However, the P-wave minimum was not found to differ between baseline and during balloon occlusion. These data demonstrate that prolongation of P-wave dispersion might be a simple and useful additional marker of myocardial ischemia during PCI.
Budeus et al. 17 examined the incidence of atrial late potentials in patients with a proximal stenosis of the right coronary artery and new onset of AF. They also investigated the antiischemic effect of a successful percutaneous transluminal coronary angioplasty (PTCA) of the right coronary artery. After successful PTCA, only three of their 15 patients were affected after one day, as well as after one month. None of the patients with a history of AF suffered from an arrhythmic recurrence within the following 6 months after successful PTCA. In that study, stenosis of the right coronary artery was associated with positive atrial late potentials. The authors concluded that a successful PTCA of the right coronary artery eliminates pre-existent atrial late potentials and may reduce the risk of AF. mortality was attenuated by improved treatment [18][19][20] . Randomised studies performed in the past few years have shown that PCI is a more effective reperfusion strategy than intravenous thrombolysis 21,22 . Therefore, the incidence of AF may have decreased and the prognostic significance of AF may have been attenuated in patients with AMI who underwent PCI 4 . However, little is known concerning the incidence of AF and its effects on the prognosis of patients with AMI who are treated with PCI.

Atrial Fibrillation in
A study from Akdemir and coll. 23 was conducted to compare the effects of reperfusion either by thrombolytic therapy or primary PTCA on P-wave duration and dispersion in patients with acute anterior wall MI. The Authors evaluated 72 consecutive patients, retrospectively, who had experienced an acute anterior wall MI for the first time. Patients were grouped according to the reperfusion therapy, PTCA versus thrombolytic therapy. There were no significant differences between the groups regarding age, gender, left ventricular ejection fraction (LVEF), left atrial diameter and volume, cardiovascular risk factors, and duration from symptom onset to treatment. P-wave dispersions and P-wave durations were significantly decreased after PTCA. In that study, primary PTCA reduced the incidence of AF by decreasing the P-wave maximum and P-wave dispersion.
Gorenek and coll. 24 examined the coronary angiographic findings of patients who developed AF during acute MI, and the effects of primary PCI and thrombolytic therapy for restoration of sinus rhythm. This study consisted of 52 patients with acute MI who underwent primary PCI or had thrombolytic therapy and developed AF during the first 12 h of hospitalisation. On admission, and 1 month later, coronary angiography was performed in all patients. In 26 of the 52 patients primary PCI was performed and in the other 26 patients thrombolytic therapy was applied (streptokinase or r-TPA) following angiography. Right coronary artery occlusions were the most frequent causes of AF (73%). In repeated coronary angiography, the coronary artery affected by the infarct was still totally occluded in five patients in the primary PCI group and eight patients in the thrombolytic therapy group (P < 0.01). At least TIMI-3 flow was observed in rest of the patients. Twenty-one patients in PCI group, and 16 patients in thrombolytic therapy group were in sinus rhythm (SR) at the time of second coronary angiography, although there was no difference between the LVEFs of the groups, as determined by echocardiography at the time of the first coronary angiography. However, the LVEF of patients in the PCI group was higher at the time of second angiography. The authors concluded that the data showed that, because the patency of the infarct-related artery was better with primary PCI, this mode of treatment was superior to thrombolytic therapy in restoring sinus rhythm in acute MI patients.

Recommendations for Management
Post-PCI AF has a propensity to revert spontaneously over a period of minutes to hours, so that, usually, it does not require immediate treatment unless it produces ischemia or hemodynamic instability. Specific recommendations based on trials in international literature for therapy in these patients, are nowadays preliminary and based on consensus, since no adequate trials will have tested alternate strategies.
Electrical cardioversion is very rarely required. But, when haemodynamic decompensation is prominent, electrical cardioversion is indicated, beginning with 50-100 joules with gradual increase if the initial shock is not successful. When necessary, a beta-blocker can be used for rate control, because of the combined effects of ischemia and sympathetic tone, which is usually increased in patients with AF. If an intravenous beta-blocker is preferred but it is uncertain whether such therapy will be tolerated by the patient, esmolol may be cautiously administrated since its very short half-life permits a therapeutic trial to be performed at reduced Indian Pacing and Electrophysiology Journal (ISSN 0972-6292), 7(1): 50-60 ( risk. If esmolol is tolerated, then a moderate or long-acting beta-blocker can be given. These drugs can be also administered in combination. Intravenous doses of verapamil or diltiazem are attractive alternatives because of their ability to slow the ventricular rate promptly, but they should be used with caution in patients with pulmonary congestion. Due to the increased risk of embolism, intravenous anticoagulation with heparin should be instituted in the absence of any contraindications, moreover if AF is still present while the patient is in the coronary care unit or in his or her room. Amiodarone and dofetelide are also effective for acute control of the ventricular response, but generally are not recommended as the drug of choice for rate control. Digoxin is one of the drugs of choice and can be used especially in patients with congestive heart failure. Atrial flutter is generally well tolerated and also tends to revert spontaneously; when necessary, it can be treated with either burst atrial pacing or electrical or pharmacologic cardioversion.

Conclusions
Atrial flutter may occur as a complication of PCI, but most of the time the patients' characteristics play important roles in the occurrence of this type of arrhythmia. For instance, ongoing acute MI can be the real reason for AF. Generally, AF tends to revert spontaneously, but treatment should be given promptly when necessary. If the patient is compromised by ventricular rate or by the loss of atrial contribution to cardiac output, synchronised DC cardioversion should be performed without delay. Intravenous beta-blockade can be effective for acute rate control. Calcium-channel blockers can be administered to promptly control ventricular rate. Digoxin, amiodarone and dofetilide are the drugs of choice for treating patients with acute MI with heart failure.

Atrial Fibrillation after Coronary Artery Bypass Grafting
Post operative atrial fibrillation (AF) is a common complication of coronary artery bypass surgery (CABG), occurring in 5-40% of patients during the first postoperative week, depending on definitions and methods of detection. A meta-analysis of controlled randomised trials confirmed that in trials using 24-h Holter ECG monitoring, the incidence of supraventricular arrhythmias was higher with Holter recordings (41.3%) than in trials with-out (19.9%) 25 . Despite recent improvements in surgical techniques and postoperative patient care, the incidence of postoperative AF seems to increase, most likely related to the existence of an increasing number of elderly patients with co-morbidities. In the majority of cases postoperative AF is transient and not life-threatening, although it may cause marked subjective symptoms, congestive heart failure, hypotension, and ischaemia, requiring pharmacological treatment or electrical cardioversion, resulting in prolonged hospital stay and additional costs in medical care 26 .
Stroke is a major adverse event, complicating the immediate outcome of CABG in about 2% of cases. AF was reported to be a major determinant of stroke after CABG, preceding the occurrence of neurological complications in approximately 37% of the patients 27 . Apart from a higher risk of stroke (odds ratio, OR 2.02), postoperative AF was associated with greater inhospital mortality (OR 1.7) and worse survival (74% versus 87%) at long-term follow-up (4-5 years) 26 . In a multivariate analysis it was an independent predictor of long-term mortality 26 . The complexity of distinguishing the intrinsic hazards due to postoperative AF from the risks related to its aetiological factors and treatment should, however, be recognised in this retrospective cohort study.
The multifactorial. Since risk stratification strategies for patients undergoing CABG could lead to more targeted preventive or therapeutic interventions, large number of trials have aimed at identifying risk factors for the development of postoperative AF. Risk factors associated with AF include advanced age (OR for 10-year increase, 1.75); history of AF (OR 2.11) or chronic obstructive lung disease (OR 1.43); valve surgery (OR 1.74); peripheral vascular disease (OR 1.54); and postoperative withdrawal of (3-blockers (OR 1.91) or angiotensin-converting enzyme (ACE) inhibitors (OR 1.69) 26,28 .
Among preoperative risk factors, advancing age has a significant association with the incidence of AF, a relationship that is particularly important as the number of elderly patients considered for CABG steadily increases. Advanced age was associated with increased levels of circulating norepinephrine, which could be related to imbalance in the autonomic nervous system, previously reported in some but not other studies as an independent risk factor for postoperative AF. Thoracic epidural anaesthesia, aimed at blocking excessive sympathetic activity, was, however, not effective in pre-venting postoperative AF 29 .
There is still no consensus as to whether operative clinical and/or electrocardiographic characteristics further distinguish patients who would develop postoperative AF. Prolonged Pwave duration consistent with intra-atrial conduction delay, the presence of preoperative supraventricular arrhythmias, and fluctuations in autonomic balance as measured by heart rate variability were identified in some but not other studies as independent risk factors for postoperative AF 30 .
Postoperative AF is probably the most important potentially reversible health care expenditure related to CABG. The recognition of the potential benefits of preventing AF after CABG is reflected by the large number of prophylactic strategies reported in the literature. In a meta-analysis including 42 randomised controlled trials, beta-blocking agents, sotalol, and amiodarone significantly reduced the incidence of postoperative AF compared with placebo, and with no marked difference between them 31 . The three drugs each prevented AF with the following odds ratios: beta-blockers 0.39, sotalol 0.35, and amiodarone 0.48) 31 . From the analysis of 10 pacing trials, atrial pacing was shown to be effective, with an odds ratio of 0.46 for biatrial pacing 31 . Biatrial pacing significantly reduced length of hospital stay by 1.5 days, but there was no evidence that the stroke rate was lowered. In another meta-analysis 32 evaluating the use of prophylactic anti-arrhythmic therapy (amiodarone, sotalol, procainamide, pacing) for the prevention of postoperative AF, the incidence of AF varied from 8% to 37% in the treatment groups and from 29% to 53% in the control groups, with a combined overall significant decrease of 0.52 (OR) in the treatment groups. When these studies were combined, there was 1,0±0,2 day overall decrease in length of hospital stay, but no significant effect on the incidence of stroke or mortality. Data on costs, available for five of the six studies that used amiodarone and one of the studies that used pacing, showed a combined insignificant decrease in cost 32 .
In another randomised study from Raddy and coll. 33 , amiodarone plus pacing significantly decreased the frequency of AF after open heart surgery, compared with amiodarone alone, pacing alone, and placebo. In the cost-effectiveness analysis, when compared with placebo, the probability of lower cost but higher effect (superiority) was 67% for amiodarone, 15% for pacing, and 97% for amiodarone plus pacing 33 . In the multivariate analysis, preoperative beta-blockers and amiodarone were negatively associated with hospital costs (P < 0.05). Data suggest that both amiodarone alone and the combination of amiodarone plus pacing are costeffective compared with placebo.
A meta-analysis of 8 prophylactic pacing trials 34  8565 patients, showed that prophylactic therapies (amiodarone, beta-blockers, sotalol, and pacing) favoured treatment for postoperative AF with an odds ratio of 0.43. A positive result for cost of hospitalisation in favour of treatment was achieved, but the statistic was not significant due to low power and large standard deviations. Beta-blockers had the greatest magnitude of effect across 28 trials (4074 patients), with an odds ratio of 0.35. The data for stroke favoured treatment by a non-significant effect size of 0.81. Similarly, a positive indication for length of stay was derived, but it too was not significant, with a weighted mean difference of -0.66.
Hypomagnesaemia is frequently observed after cardiac surgery and is related to the extracorporeal circulation and the use of diuretics. In a meta-analysis of 17 trials with 2069 patients 36 , magnesium supplementation reduced the risk of supraventricular arrhythmias (relative risk 0.77) but had no effect on the length of the hospital stay or mortality. Administration of prophylactic magnesium reduced the risk of postoperative AF by 29%, although the inhomogeneity among trials may limit the formulation of definitive conclusions.
The effect of cardiopulmonary bypass on the incidence of AF after CABG has been addressed in several trials. A meta-analysis 37 of all observational studies comparing cardiac pulmonary bypass (2253 patients) and off-pump techniques (764 patients) in elderly patients demonstrated a significantly lower incidence of postoperative AF (odds ratio 0.70) after offpump surgery. The results were confirmed in another meta-analysis of 37 randomised trials (3369 patients) 38 , in which off-pump CABG significantly decreased AF (OR 0.58) and hospital stay (weighted mean difference, -1.0 days) but without affecting 30-day mortality or stroke rate (OR, 0.68). It should be emphasised, though, that the lower risk profile of patients undergoing off-pump CABG could contribute to a lower AF risk.
Radiofrequency ablation of pulmonary vein triggers has had a remarkable high success rate for non-postoperative AF. Our own data showed that onset of AF after CABG was triggered by premature beats in 72% of patients with postoperative AF, which implies that atrial triggers may be important in the postoperative setting. It is, however, as yet unclear whether a surgical epicardial approach would be effective and safe if implemented during routine CABG procedures.
The importance of the parasympathetic nervous system for the initiation of AF is still incompletely understood, although it is thought to play a role in the subsets of patients with paroxysmal non-postoperative AF. Vagal post-ganglionic neurons are located in well defined anatomic fat pads situated in two posterior epicardial regions around the heart and adjacent structures. Transvenous radiofrequency (RF) ablation at such sites has resulted in vagal denervation and improved outcome in patients with non-postoperative AF subjected to circumferential pulmonary vein ablation 39 . In animal studies the destruction of an anterior fat pad shown to contain vagal neurons resulted in decreased susceptibility to AF. The anterior fat pad, located in the aortopulmonary window, was therefore studied in humans with respect to its role in postoperative AF 40 . The authors' question was whether its removal, as routinely done during the process of placing the aortic cross-clamp, would decrease subsequent AF 40 . By stimulating the anterior fat pad in patients undergoing CABG, the sinus rate was slowed with no change in PR interval, consistent with innervation of the sinus node but not the atrioventricular node 40 . Since enhanced vagal tone is pro-fibrillatory in the atria by shortening refractoriness, the underlying theory was that removal of tissue responsible for vagal atrial influences would improve AF outcome. In this randomised study, paradoxically, 37% of patients in whom the interior fat pad was dissected developed postoperative AF compared with 7% in whom the fat pad was preserved 40 . Supportive of these findings is the reported lower incidence of AF after offpump CABG, during which the anterior fat pad is often preserved 37 . Animal experiments support vagal denervation as an effective anti-arrhythmic strategy, which is consistent with the finding of a lower incidence of AF following vagal denervation during catheter ablation procedures. The importance of vagal influences and the role of the cardiac fat pads for developing postoperative AF demand further clinical research to determine the optimal surgical technique.
The class I recommendations for prevention and management of postoperative AF are: (1) an oral beta-blocker for preventing AF, unless contraindicated (Class of Evidence: A) and (2) administration of AV node blocking agents to achieve rate control in patients who develop postoperative AF (Level of Evidence: B) 41 . Class Ila recommendations are: (1) prophylactic amiodarone for patients at increased risk of developing postoperative AF (Level of Evidence: A); (2) electrical or pharmacological cardioversion with ibutilide, when reasonable, to restore sinus rhythm, as recommended for non-surgical patients (Level of Evidence: B); (3) attempt at maintenance of sinus rhythm by administration of anti-arrhythmic medications if there is recurrent or refractory postoperative AF, as recommended for patients with coronary artery disease who develop AF (Level of Evidence: B); and (4) anti-thrombotic medication in patients who develop post-operative AF, as recommended for non-surgical patients (Level of Evidence: B).